Technical Field
This disclosure relates generally to substituted 1,2,3-triazole compounds, to processes and intermediates used in their preparation, to compositions containing them and to methods of treating neurological disorders by administration of such compounds to a warm-blooded animal in need thereof.
Description of the Related Art
Essential tremor (ET) is one of the more common tremor disorders and one of the more common neurological diseases. While the disease is often called “benign”, this postural and/or kinetic tremor frequently causes difficulty with everyday tasks such as writing, pouring and eating. ET has a prevalence comparable to that of epilepsy and greater than both Parkinson's disease and Alzheimer's disease. The incidence of ET rises with increasing age and a family history of ET appears to correlate with a younger onset of disease. Pharmacological treatments of this disorder are limited due to variable effectiveness, occurrence of side effects and lack of understanding of the pathophysiology of the disease.
ET has variable clinical expression characterized by a postural and/or kinetic tremor with a frequency range between 4 and 12 Hz. The tremor frequency generally decreases over time while amplitude increases. Approximately 90% of patients have tremor in their upper extremities, 30% have a head tremor, 20% voice tremor, 10% face or jaw tremor and 10% lower body tremor. Additionally, recent studies indicate higher rates of mild cognitive changes, depression, anxiety, social phobias and olfactory and hearing deficits in ET patients compared to normal controls (see, e.g., Zesiewicz et al., Neuropsychiatric Disease and Treatment, 2010:6, 401-408).
The oldest anti-tremorgenic agent in the management of ET is ethanol. While showing some beneficial effects, this therapy is impractical due to addiction issues and serious drawbacks with long-term ethanol use (see, e.g., Iseri et al., Neuropharmacology, 2011, 61:715-723).
Although many medications have been tested, the pharmacological treatment of ET is not optimal. Two medications are considered first-line treatments: propranolol, a nonselective beta blocker which is the only FDA approved agent for ET; and primidone, an antiepileptic drug. In addition to side effects which include bronchoconstriction, bradycardia, hypotension, depression and fatigue for propranolol and sedation, dizziness, fatigue, nausea and depression for primidone (see, e.g., Abboud et al., Cleveland Clinic Journal of Medicine, 2011 78:12:821-828), neither drug reduces tremor levels to asymptomatic levels nor is effective in more than about half of patients with disease.
In addition to the first-line treatments for ET noted above, over the last decade several other therapies have been studied, most of which are older drugs repurposed for ET such as antiepileptic agents, gabapentin, topiramate, zonisamide, levitiracetam, phenobarbital, pregabalin and lacosamide; calcium antagonists flunarizine and nicarpine; benzodiazepines such as alprazolam; antidepressant mirtazapine; and agents such as sodium oxybate, T-2000 and 1-octanol. Further botulinum toxin injection has been the subject of several small studies and may be useful for intractable head and voice tremor (see, e.g., Shill, Clinical Medicine: Therapeutics (2009) 1: 613-620, Sadeghi et al., Drugs 2010; 70(17):2215-2228).
Surgical procedures may also provide treatment for severe and refractory ET. Deep Brain Stimulation of the ventral intermediate thalamus involves surgery to implant an electrode and a pulse generator. Thalamotomy is a stereotactic procedure that creates a lesion in the ventral intermediate nucleus of the thalamus. Side effects and adverse events limit this surgery to patients who are not responsive to pharmacotherapy (see, e.g., Zesiewicz et al., Neuropsychiatric Disease and Treatment, (2010) 6:401-408).
Epilepsy is a brain disorder characterized by periodic and unpredictable seizures. The behavioral manifestations of epileptic seizures in human patients range from mild twitching of an extremity to loss of consciousness and uncontrollable convulsions. Up to 1% of the population is afflicted, making epilepsy one of the most common neurological problems and a considerable economic burden on society. Despite the considerable progress in our understanding of the pathophysiology and pharmacotherapy of seizures and epilepsy, the cellular basis of human epilepsy remains an enigma. In the absence of etiological understanding, approaches to pharmacotherapy have been directed to the control of symptoms; namely, the suppression of seizures. More concerning is that current antiepileptic drugs do not halt the underlying natural progression of the disorder.
Over the years, there has been considerable success in the development of novel antiepileptic drugs (AED) along with new improved formulations. These include older “first generation” drugs such as carbamazepine, phenobarbital, valproic acid and newer, “second generation” drugs such as lamotrigine, vigabatrin, tiagabine, topiramate, gabapentin and levetiracetam (see, e.g., Brazil et al., Ann. Rev. Med., 1998, 49:135-162; McCabe P H., Expert Opinion. Pharmacother., 2000, 1:633-674]. The selection of an antiepileptic drug for treatment is predicated on its efficacy for the specific type of seizures, tolerability and safety (see, e.g., Regesta et al., Epilepsy Res., 1999, 34:109-122; Kwan et al., Engl. J. Med., 2000, 342:314-319).
Status epilepticus (SE) is a life threatening condition characterized by a prolonged state of continuous convulsions resulting in significant morbidity and mortality. SE is defined as seizure activity lasting for 30 minutes or longer without regaining consciousness. Treatment should be initiated promptly since prolonged SE may result in death, progressive brain damage or develop into the difficult to treat refractory SE. As many as 200,000 people are affected in the U.S. annually, with as many as 55,000 deaths. Causes of SE include both acute health problems such as stroke, metabolic disturbances, infections, head trauma and drug interactions and chronic processes such as pre-existing epilepsy, discontinuation of drug therapy and central nervous system tumors (see, e.g., Deshpande et al., Front Neurol (2014, 5:11).
SE is categorized as convulsant or nonconvulsant, both of which require prompt treatment to prevent death and brain injury. The pathophysiology of SE is not clearly understood. After medical stabilization of the patient a first line treatment involves intravenous or intramuscular administration of a benzodiazepine such as midazolam, diazepam or lorazepam. Second line therapy involves the additional administration of phenytoin, fosphenytoin, phenobarbital or valproic acid. Approximately 40% of SE cases do not resolve to this treatment and are termed refractory. Refractory SE is generally treated with anesthetics such as propofol or phenobarbital. (see, e.g., Reddy et al., Int. J. Mol. Sci. 2013, 14:18284-318).
Nerve agents inhibit acetylcholinesterase resulting in elevated acetylcholine levels in the nervous system. Ensuing cardiorespiratory depression and status epilepticus may lead to death or brain damage in affected individuals (see, e.g., Apland et al., J Pharmacol Exp Ther 2013, 344:133-40).
While significant strides have been made in this field, a need remains for small molecules effective in the treatment of neurological disorders and diseases, especially essential tremor, epilepsy, status epilepticus, and/or nerve agent exposure. These small molecules may reduce some of the side effects and limitations of current drug therapies such as treatment of refractory patients, reduced sedation, cognitive and behavioral effects, drug/drug interactions, and teratogenicity/genotoxicity concerns. The present disclosure fulfills these needs and provides other related advantages.